多巴胺和5-羟色胺受体系统参与脊髓损伤后继发性骨质疏松症发病：新理论和诊疗策略

doi:10.3969/j.issn.2095-4344.2016.51.020

中国组织工程研究 ›› 2016, Vol. 20 ›› Issue (51): 7731-7737.doi: 10.3969/j.issn.2095-4344.2016.51.020

• 组织构建综述 tissue construction review • 上一篇下一篇

多巴胺和5-羟色胺受体系统参与脊髓损伤后继发性骨质疏松症发病：新理论和诊疗策略

张淼1，张旭然1，李锐2，孙羽3

1阜新市中心医院骨科三病房，辽宁省阜新市 123000；2吉林大学第二医院骨科诊疗中心，吉林省长春市 130041；3中国医科大学附属第一医院骨外科(关节外科和运动医学病房)，辽宁省沈阳市 110001

收稿日期:2016-10-29 出版日期:2016-12-09 发布日期:2016-12-09
通讯作者: 孙羽，硕士，讲师，主治医师，中国医科大学附属第一医院骨外科（关节外科和运动医学病房），辽宁省沈阳市 110001
作者简介:张淼，男，1977年生，辽宁省阜新市人，2009年中国医科大学毕业，硕士，副主任医师，主要从事骨关节外科、神经损伤修复及再生研究。
基金资助:
国家重点基础研究发展计划(973计划)项目(2014CB542200)

Dopamine and 5-hydroxytryptamine signaling pathways in the pathogenesis of spinal cord injury-induced osteoporosis: new theory and novel therapeutic strategies

Zhang Miao1, Zhang Xu-ran1, Li Rui2, Sun Yu3

1 Third Orthopaedics Ward, Fuxin Central Hospital, Fuxin 123000, Liaoning Province, China
2 Bethune Second Hospital, Changchun 130041, Jilin Province, China
3 Department of Orthopaedics (Joint Surgery and Sports Medicine), First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China

Received:2016-10-29 Online:2016-12-09 Published:2016-12-09
Contact: Corresponding author: Sun Yu, Master, Lecturer, Attending physician, Department of Orthopaedics (Joint Surgery and Sports Medicine), First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
About author:Zhang Miao, Master, Associate chief physician, Third Orthopaedics Ward, Fuxin Central Hospital, Fuxin 123000, Liaoning Province, China
Supported by:
the National Key Basic Research Development Program of China (973 Program), No. 2014LB542200

摘要/Abstract

摘要：

文章快速阅读：

文题释义：
脊髓损伤导致的骨质疏松症：发生于脊髓损伤后的继发性骨质疏松症，既往有观点认为是由于神经损伤后长期肌肉骨骼系统功能障碍导致的失用性疾病，近年研究则提示参与骨代谢调节的神经递质可能在疾病进展中作用更为重要。该类继发性骨质疏松症在脊髓损伤患者中其实际发病率高，但诊断率低，临床治疗手段有限。
多巴胺和5-羟色胺受体系统：多巴胺和5-羟色胺为中枢神经系统内的重要神经递质，同时均对机体骨代谢具有调控作用，在脊髓损伤后多巴胺和5-羟色胺的正常传输及相应受体系统的功能状态变化与多项病理生理改变和临床并发症相关。

摘要
背景：近年来有新的基础医学和临床研究结果提示，脊髓损伤后早期即出现骨吸收增加和骨量下降，其病理阶段起始早于单纯失用性骨质疏松，表明有其他机制参与脊髓损伤导致的骨质疏松症的发病过程。
目的：通过文献检索，分析中枢神经系统内主要神经递质包括多巴胺和5-羟色胺及其受体系统对骨代谢的影响、在脊髓损伤后的病理变化以及相关受体作为靶点对脊髓损伤的治疗性研究，综述相关基础和临床科研现状及进展，提出关于脊髓损伤导致的骨质疏松症发病机制的新理论和诊疗策略。
方法：检索1967年1月至2016年8月PubMed数据库和Embase数据库中有关脊髓损伤后继发性骨质疏松症与神经递质多巴胺和5-羟色胺及其受体系统相关的基础和临床研究文献。英文检索词包括“spinal cord injury；osteoporosis；dopamine；serotonin； 5-hydroxytryptamine”。排除与研究目的无关、相关性差或内容重复的研究。
结果与结论：多巴胺和5-羟色胺是中枢和外周神经系统主要神经递质，对骨吸收和重建均起调节作用。脊髓损伤发生后中枢神经系统内下行的多巴胺和5-羟色胺作用途径受损，随后多巴胺受体系统和5-羟色胺受体系统的作用变化将导致骨吸收增加和骨重建受损。通过了解脊髓内多巴胺受体系统和5-羟色胺受体系统在脊髓损伤导致的骨质疏松症发病过程中的作用，推测可将多巴胺和5-羟色胺受体作为治疗靶点。现有研究指出部分多巴胺和5-羟色胺受体激动剂可改善脊髓损伤后运动功能，提示相关制剂作用于损伤平面以下多巴胺和5-羟色胺受体同时可能抑制骨吸收并促进骨重建，为脊髓损伤导致的骨质疏松症、其他类型继发性骨质疏松症和原发性骨质疏松症提供全新的预防或治疗途径。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
ORCID: 0000-0002-8330-942X(Sun Yu)

关键词: 组织构建, 骨组织工程, 脊髓损伤, 骨质疏松, 骨吸收, 骨重建, 多巴胺, 5-羟色胺, 神经递质, 受体激动剂

Abstract:

BACKGROUND: Current basic and clinical research have showed that increases in bone resorption and bone loss accur earlier after spinal cord injury (SCI) than disuse atrophy, revealing that other mechanisms are involved in the pathogenesis of the SCI-induced osteoporosis (SIO).
OBJECTIVE: To introduce the current lab and clinical research progress in SIO focusing on the functional changes of two major neurotransmitters in the spinal cord, including dopamine (DA), 5-hydroxytryptamine (5-HT) and their receptors, as well as their regulatory functions on bone metabolism, aiming at finding a new treatment strategy for SIO.
METHODS: A computer-based online search in PubMed and Embase databases was conducted for clinical and basic research related to SIO published from January 1967 to August 2016, using the keywords of “spinal cord injury; osteoporosis; dopamine; serotonin; 5-hydroxytryptamine” in English. Irrelevant, poorly related and repetitive studies were excluded, and finally 41 eligible articles were included.
RESULTS AND CONCLUSION: DA and 5-HT are major neurotransmitters in the central nervous system, both involving in the regulation of bone remodeling. After SCI, loss of innervation and descending neurotransmitters especially DA, 5-HT and subsequent deregulation of their receptors are responsible for the onset of post-traumatic bone loss. The above research progress, in combination with the emerging clinical and lab investigations targeting 5-HT, DA and their receptors for improving neural functions after SCI, provides possible therapeutic pathways for SIO.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Spinal Cord Injuries, Osteoporosis, Dopamine, Serotonin, Tissue Engineering

中图分类号:

R318

张淼，张旭然，李锐，孙羽. 多巴胺和5-羟色胺受体系统参与脊髓损伤后继发性骨质疏松症发病：新理论和诊疗策略[J]. 中国组织工程研究, 2016, 20(51): 7731-7737.

Zhang Miao, Zhang Xu-ran, Li Rui, Sun Yu. Dopamine and 5-hydroxytryptamine signaling pathways in the pathogenesis of spinal cord injury-induced osteoporosis: new theory and novel therapeutic strategies[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(51): 7731-7737.

图/表（结果） 1

DA and 5-HT as neurotransmitters in spinal cord and their roles in modulating bone metabolism

In SCI patients with lower limb paralysis, their upper extremities with biological loading conditions above spinal cord lesion level were found decrease in bone mineral content^[14], which indicated that neurological and hormone disorders associated with SCI could be the underlying mechanism of osteoporosis, especially the changes in DA and 5-HT. This was also supported by the reduced anabolic functions of osteoblasts and magnified activity of osteoclasts showed by in vivo research of SCI^[15].

5-HT is a multifunctional molecule targeting on multiple tissues, converted from 5-hydroxy-L-tryptophan (5-HTP) in a reaction catalyzed by tryptophan hydroxylase (Tph)^[16]. 5-HT is mostly gut-derived, produced by the enterochromaffin cells in duodenum, mediating peristalsis and cardiovascular functions^[17]. While in the spinal neural networks, 5-HT is synthesized in

brainstem as an important neurotransmitter regulating locomotion system^[18]. 5-HT exerts biological effects via a large group of membrane

binding receptors, ranging from 5-HT₁ to 5-HT₇. The action duration of 5-HT is regulated by the 5-HT transporter (5-HTT) which uptakes released 5-HT to control its extracellular concentrations^[19]. 5-HT in the spinal cord regulates motor system via serotoninergic neurons in the medulla, so SCI leads to extremity unloading with depletion of 5-HT from the brainstem, reducing the motor neuron excitability, and elevating expression of 5-HT receptors with functional disorders^[20]. Moreover, recent studies showed that 5-HT provides neural modulations of bone metabolism in a bimodal manner. Both brain- and gut-derived 5-HT participate in the constant, dynamic and balanced process of bone remodeling, but through different targets^[21]. The brain-derived 5-HT regulates bone formation positively, while peripheral gut-derived 5-HT inhibits bone mass accrual by stimulating periosteal fibroblasts proliferation and modulating osteoblasts in response to mechanical stress^[22].

DA acts on a family of G-protein coupled receptors named dopaminergic receptors (DRs), including five different subtypes that can be further categorized into two groups according to their pharmacological properties: D1-like (D1 and D5) receptors and D2-like (D2, D3 and D4) receptors^[23]. In the vertebrates, it is believed that the spinal DA is produced by dopaminergic diencephalospinal tract (DDT)^[24], and the location and projections of dopaminergic neurons in DDT follows a conserved pattern. DA receptors are distributed at all levels of the spinal cord with varied distribution characteristics reported among studies regarding different animal species^[25]. Pathological lesions of dopaminergic neurons will lead to the restless leg syndrome in adults that can be treated with levodopa or D2/D3 receptor agonists^[26]. Besides, locomotive functions in the brain and spinal cord, DA also is showed to play an important role in the process of bone remodeling^[27-28]. Some researchers demonstrated the expression of all DR subtypes in the osteoclast precursor cells, and further proved the involvement of dopaminergic signaling pathways in the process of osteoclastogenesis and D2-like agonists could effectively reduce TRAP-positive cells and pit formation in vitro that can be reversed by pretreatment of D2-like receptor antagonists^[29]. Furthermore, other studies also showed that DA could regulate immune cell functions, via binding D1-like receptors on T cell membranes, inducing activation of cAMP and interleukin-6 production, which will promote osteoclast differentiation and bone loss in rheumatoid arthritis^[30].

Clinically, therapeutic drugs targeting 5-HT, DA and their receptors are commonly prescribed worldwide for mental disorders, such as selective serotonin reuptake inhibitors (SSRIs) for depression, D2 receptor antagonists for psychosis, both achieving satisfactory therapeutic efficacy. As 5-HT and DA both play roles in bone metabolism, their potential side-effects to human skeletal system should be taken into consideration for patients with long-term use. Clinical observations have witnessed the bone loss and high risk of fractures in depression patients, associated with long-term use of SSRIs, suggesting the negative effects of 5-HT signaling blockage, and the mechanism involved in elevating local 5-HT concentration in peripheral tissue^[31-33]. Moreover, several clinical studies showed that anti-psychotic drugs such as D2 receptor antagonists were associated with decreased BMD in schizophrenia patients^[34-36], which has also been proved by in vivo experiments in rats^[37]. On the one side, these studies further demonstrated the importance of 5-HT and DA in bone metabolism, while on the other side suggested novel therapeutic strategies for osteoporosis especially SIO, where neurotransmitters and their receptors may play more fundamental roles than other factors such as age, sex hormones and muscular disuse ^{[21-22, 27-37]}.

Targeting DA, 5-HT and their receptors: potential therapeutic pathways for locomotion improvement in SCI and SIO (Figure 2)

Although active in modulating bone metabolism, the most important function of DA and 5-HT are as neurotransmitters. Both clinical and lab studies demonstrated that the disruption of 5-HT and DA pathways is directly related to the motor function impairment after SCI, and the re-activation of certain DA and 5-HT receptors would improve movements. For DA, the spinal dopaminergic system also plays important roles in this locomotion functions. In zebrafish, the DDT and dopaminergic system were found to be responsible for modulating the developmental mature locomotion pattern switch via spinal D4 receptor signaling pathways, the dopaminergic signaling pathways in the spinal cord are required for the mature locomotion patterns, and D4R agonist could rescue the mature locomotion in spinalized animals^[24]. In a mouse model of complete spinal cord transection, D1/D5 receptor agonist induced locomotor-like movements which can be destroyed by D1/D5 antagonist pretreatment^[38]. Same effects could be observed in mouse lacking D5 receptors, but selective D2/D3/D4 agonists could not elicit obvious reactions, indicating that D1 receptors are responsible for the movement activation^[39]. This is supported by another research showing that D1 receptor agonist could significantly reduce the levels of inflammatory cytokines, attenuate histopathology and promote locomotion recovery in a rat model of SCI ^[40].

As to 5-HT, an in vivo investigation of pharmacotherapy with injection of 5-HT agonists combined with passive exercise daily demonstrated promoted motor cortex reorganization in a rat model of mid-thoracic level spinal cord transection^[41]. Another research revealed a transient acute increased expression of 5-HT_1A receptor associated with locomotion recovery in a complete SCI model of lampreys, indicating possible mechanism of SCI recovery in this animal model and 5-HT_1A as the potential target^[42]. In addition, 5-HT_2B has been demonstrated to mediate 5-HT production by spinal cord neurons after SCI, which further explains the origins of residual 5-HT detected in previous studies^[43]. Besides, agonists of 5-HT₂ receptors could stimulate motor-neuron output, and the activation of 5-HT₂ and 5-HT_1A_/7 receptors also activate the spinal cord circuitry for locomotion^[44]. In another mice model of complete SCI, single administration of selective D1/D5 or 5-HT_1A_/7 receptor agonist induced hind limb movement independently but with minor effects^[38]. However, combined administration of the agonists induced significantly increased movements even with weight bearing capabilities, showing a synergistic effect^[38].

As the primary impact of SCI lies in the profound damage in volitional movement, most research investigating SCI focused on the rehabilitation of motor functions. So DA, 5-HT and their receptors have been extensively investigated in SCI research aiming at improving motor functions with positive results, as the depletion of neurotransmitters such as 5-HT and DA, is an important mechanism. At the same time, it is practical to evaluate whether related agents will provide bone protection effects in SIO, because 5-HT and DA also regulate bone metabolism and bone loss initiates almost immediately after SCI together with motor damage, continuing progressing in chronic cases^[45]. Possible intervention strategies may include supplementing 5-HT, DA or precursors, and modulating receptors via administration of specific agonists. However, the balanced roles played by DA and 5-HT also pose great challenge, for their functions in different organs may act via independent pathways and with complex or even contradictory results. For example, though certain chemical agents such as 5-HT_2C receptor agonists theoretically could increase bone mass by simulating the effect of brain-derived 5-HT signaling, it also regulates sympathetic system in peripheral tissue and thus the related clinical evaluations are limited^[46]. Interestingly, certain 5-HT₂ antagonist is found also to have bone protection effects by reducing bone atrophy in patients with complex regional pain syndrome that are commonly seen in central and peripheral nerve injuries^[47]. Thus there is still much uncertainty in its therapeutic effects.

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引言

As it has been reported that the incidence of bone fracture in patients with spinal cord injury (SCI) could be more than 7% annually^[1], and clinical follow-up studies revealed the overt decrease in bone mineral density (BMD) involving both trabecular and cortical bone in SCI patients^[2], the gap between clinical osteoporosis diagnosis and the high occurrence of bone fractures in SCI victims has arose more attention^[3].

SCI-induced osteoporosis (SIO) was considered to be a result of disuse atrophy and the change of unloading status of sub-lesional extremities, which has been emphasized for treatment, including varied physical therapies and rehabilitation programs with different outcomes^[4-6]. Bisphosphonate analogues

have been reported to effectively alleviate BMD decrease and subsequent bone loss in SCI patients and are widely used^[7]; while the efficacy was reported to be decreased when combined with other drugs^[8]. Parathormone (PTH) is recommended as the anabolic therapy, but possesses relatively narrow indications and is restricted to be used within 2 years^[9]. Monoclonal antibodies, such as anti-sclerostin and anti-RANKL agents show promising results, however, there is a tendency to cause autoimmune, infectious diseases and cardiovascular system toxicity^[10-12]. Besides, previous in vivo research also demonstrated that monoclonal antibodies may expose no influence on chronic SCI patients^[13].

Our article introduces the current basic and clinical research progress in SIO focusing on the functional change of two major neurotransmitters in the spinal cord, including dopamine (DA), 5-hydroxytryptamine (5-HT) and their receptors, and points out new theories of pathogenesis in SIO and novel therapeutic strategies.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

多巴胺和5-羟色胺受体系统参与脊髓损伤后继发性骨质疏松症发病：新理论和诊疗策略

Dopamine and 5-hydroxytryptamine signaling pathways in the pathogenesis of spinal cord injury-induced osteoporosis: new theory and novel therapeutic strategies

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